Hippocampal-Avoidance Using Intensity-Modulated Radiation Therapy for the Treatment of Low-Grade Glioma

PRIMARY OBJECTIVE:

I. To determine the feasibility of hippocampal-avoidance (HA) using proton therapy in suprasellar or midline low-grade gliomas (LGGs).

SECONDARY OBJECTIVES:

I. To estimate the 3-year event free survival (EFS) of LGG treated with HA.

II. To estimate the change in California Verbal Learning Test short-term delay (CVLT-SD) scores from baseline to 3 years and from baseline to 5 years.

III. To compare CVLT-SD and Cogstate neurocognitive scores in patients with proton therapy plans that: (1) meet first priority radiation therapy (RT) dose constraints, (2) meet second priority RT dose constraints but not first priority RT dose constraints, and (3) that did not meet either first or second RT priority dose constraints.

EXPLORATORY OBJECTIVES:

I. To describe the change in overall cognitive performance from baseline to 3 years and from baseline to 5 years with an age appropriate battery, including gold standard measures shown in the published studies to be sensitive to attention, memory processing speed and executive function that will afford comparison to historical controls.

II. To characterize longitudinal changes in connection strength within brain networks in the first 3 years after proton therapy and to investigate associations between these changes and neurocognitive performance with focus on the hippocampi.

III. To correlate the distribution and change in L-methyl-11C-methionine positron emission tomography (MET-PET) uptake to tumor progression from baseline to 3 years and to investigate whether cases of pseudoprogression exhibit a differential pattern of uptake and distribution than do cases of true progression after controlling for histology.

IV. To investigate the effect of BRAF alteration, tumor histology and tumor location on progression-free survival (PFS) and overall survival (OS) in a prospective cohort of patients treated in a homogenous manner.

V. To investigate whether the methylation profiles of LGG differ across tumor locations (thalamic/midbrain versus [vs.] hypothalamic/optic pathway vs. others) and histologies (pilocytic astrocytoma vs. diffuse astrocytoma vs. others), which in conjunction with specific genetic alterations may stratify patients into different subgroups and highlight different therapeutic targets.

VI. To record longitudinal measures of circulating tumor (ctDNA) in plasma and correlate these measures with radiographic evidence of disease progression.

VII. To bank formalin-fixed, paraffin-embedded (FFPE)/frozen tumors and whole blood from subjects for subsequent biology studies not currently defined in this protocol.

VIII. To quantify and characterize tumor infiltrating lymphocytes (TILs) and to characterize the epigenetics of T cells and the T-cell receptor repertoire within the tumor microenvironment.

IX. To estimate the cumulative incidence of endocrine deficiencies, vision loss, hearing loss and vasculopathy after proton therapy and compare these data to those after photon therapy.

OUTLINE:

Patients undergo 29-30 fractions of intensity-modulated radiation therapy over 30-50 minutes 5 days per week, Monday-Friday for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years and then every 6 months for up to 3 years.